Project Summary/Abstract Maintenance of skeletal muscle is essential for health and plays a significant role in quality of life. Inactivity promotes skeletal muscle atrophy that not only reduces mobility but also increases the propensity to develop metabolic and cardiovascular diseases. Although skeletal muscle atrophy has broad clinical impact in the increasingly sedentary and aging population, a pharmacologic therapy for muscle mass loss does not exist. Reactive oxygen species (ROS) is one possible mechanism that induces muscle atrophy by accelerating proteolysis and depressing protein synthesis. However, the molecular origin of disuse-induced ROS is unknown. In this application, we will test our hypothesis that changes in mitochondrial phospholipid composition is a mechanism by which disuse increases ROS and contributes to muscle atrophy. Preliminary data show that mouse hindlimb unloading is sufficient to reduce the proportion of mitochondrial phosphatidylethanolamine (PE). PE is a conically-shaped phospholipid that forms membrane curvatures and is known to congregate at cristae where it facilitates enzymes of electron transport system (ETS). Skeletal muscle-specific ablation of mitochondrial PE was sufficient to increase ROS and promote atrophy. In this proposal we will: 1) determine whether mitochondrial ROS-scavenging is sufficient to prevent muscle atrophy induced by mitochondrial PE depletion, and 2) determine whether increasing mitochondrial PE is sufficient to protect mice from disuse-induced ROS production and atrophy. Findings from these studies have substantial implications on the molecular mechanism responsible for muscle atrophy and how we develop treatment for loss in skeletal muscle mass and contractile function.